Promoter polymorphisms in the MATP (SLC45A2) gene are associated with normal human skin color variation
Promoter polymorphisms in the MATP (SLC45A2) gene are associated with normal human skin color variation
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DOI：
10.1002/humu.20504
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发表时间：
2007-07-01
期刊：
影响因子：
3.9
通讯作者：
van Daal, Angela
中科院分区：
文献类型：
--
作者：
Graf, Justin;Voisey, Joanne;van Daal, Angela
人类色素沉着是一种复杂的生理特征，其中膜相关转运蛋白（MATP）在细胞内加工和运输黑素体蛋白中起着重要作用。最近，MATP的致病性突变已被证明可导致4型眼皮肤白化病，而已知其他多态性在正常色素沉着变化中起作用。我们之前报道了两种编码区多态性与白种人头发、皮肤和眼睛颜色的显著关联。在这里，我们鉴定了两个新的转录起始位点和一个新的复制位点（c - 1176_1174dupaat）。对来自5个不同人群（529名高加索人、38名亚洲人、46名非洲裔美国人、47名澳大利亚土著人和40名西班牙巴斯克人）的700名个体进行了已知启动子多态性c- 1721c > G （rs13289）和c- 1169g > A （rs6867641）以及c- 1176_1174dupaat的基因分型。三种多态性的等位基因频率在不同人群间存在显著差异。在白种人中，-1721G、+dup和-1169A等位基因与橄榄色皮肤显著相关。这三个启动子多态性彼此之间存在连锁不平衡，但与先前报道的两个编码区多态性之间不存在连锁不平衡。对黑色素瘤细胞系的功能分析表明，启动子单倍型-1721G， +dup， -1169A显著降低了MATP转录。本报告通过鉴定白种人MATP等位基因与肤色变异之间的关联，并证明了这些多态性的功能意义，进一步证明了MATP参与正常色素沉着变异。
Human pigmentation is a complex physical trait in which the membrane-associated transporter protein (MATP) plays an important role as it is involved in intracellular processing and trafficking of melanosomal proteins. Recently, pathogenic mutations in MATP have been shown to cause oculocutaneous albinism type 4, while other polymorphisms are known to have a role in normal pigmentation variation. We previously reported significant associations of two coding region polymorphisms with hair, skin, and eye color in Caucasians. Here we characterize the promoter region of MATP identifying two new transcription start sites and a novel duplication (c.-1176_-1174dupAAT). A total of 700 individuals from five different population groups (529 Caucasians, 38 Asians, 46 African Americans, 47 Australian Aborigines, and 40 Spanish Basques) were genotyped for known promoter polymorphisms c.-1721C > G (rs13289) and c.-1169G > A (rs6867641), as well as c-1176_-1174dupAAT. Allele frequencies of all three polymorphisms were significantly different between population groups. In Caucasians, the -1721G, +dup, and -1169A alleles were significantly associated with olive skin color. The three promoter polymorphisms were found to be in linkage disequilibrium with each other but not with the two previously reported coding region polymorphisms. Functional analyses in a melanoma cell line showed that the promoter haplotype -1721G, +dup, -1169A significantly decreased MATP transcription. This report provides further evidence for the involvement of MATP in normal pigmentation variation by identifying associations between MATP alleles and skin color variation in Caucasians and demonstrating a functional significance of these polymorphisms.